Background: In the Strong Heart Study (SHS), chronic low-to-moderate arsenic exposure in drinking water is associated with an increased risk of cardiovascular disease, diabetes, kidney disease, and cancer in American Indians (AI) from Arizona, Oklahoma, and North/South Dakota. Effective interventions are urgently needed to mitigate arsenic exposure in AI communities who rely on private wells as the main source of water for drinking and cooking. Objective: The purpose of the study is to design, implement, and evaluate multi-level participatory interventions that can lead to a sustained reduction in arsenic exposure in AI communities in North/South Dakota that remained exposed to elevated arsenic levels in drinking water. Preliminary studies: In a recent pilot study, >50% of private wells from Spirit Lake (North Dakota) and Pine Ridge (South Dakota) had arsenic levels in drinking water exceeding the US Environmental Protection Agency standard (10 g/L). Design and setting: This study will be divided into 3 phases: (1) Formative research and planning; (2) Implementation and evaluation of the multi-level intervention; and (3) Dissemination at the household, tribal, regional, and national levels. The formative research and planning phase will develop and pilot arsenic interventions through in- depth interviews and focus group discussions, a community advisory board workshop, and a pilot study. We will build local capacity to ensure the long-term sustainability of the intervention program by developing a training program for community members to test water sources for arsenic using rapid field kits, installing and maintaining point of use arsenic removal devices, and disseminating the developed health messages. During the intervention phase we will conduct a two-arm cluster-randomized controlled trial to prospectively follow 300 households and 600 participants (2 per household) to evaluate the effectiveness of the developed multi- level intervention in reducing urine arsenic concentrations and biomarkers of cardiovascular disease (cell adhesion molecules) and diabetes (glycated hemoglobin) during a 6 month period. The first arm will receive water arsenic testing and an arsenic removal device during one home visit by a community promoter (standard program). The second arm will receive water arsenic testing, an arsenic removal device, and an intensive health promotion program of 5 home visits by a community promoter (intensive health promotion program). To assess the long-term sustainability, we will measure arsenic in urine and water, and collect meter-based water use and self-reported device maintenance data 1 to 3 years after baseline. During the dissemination phase, we will work closely with tribal leaders and the Indian Health Service to disseminate study findings and develop sustainable arsenic mitigation policies to upscale the developed intervention programs to include other AI communities. Significance: This study will be the first to develop, implement, and evaluate a participatory multi-level intervention to reduce arsenic exposure from private wells in AI communities and to determine if the intervention can reduce arsenic exposure and early biomarkers of cardiovascular disease and diabetes.